This application describes a plan that combines recently developed clinical tests and laboratory methodologies to improve our ability to carry out therapeutic trials in small-fiber sensory neuropathies. This career development application will build upon the clinical expertise of Dr. Herrmann in neuromuscular disorders, electrophysiology, and peripheral nerve histopathology. The long-range goal of Dr. Herrmann is to develop a successful independent research program that includes both investigations of the pathomechanism of different small fiber sensory neuropathies and the performance of therapeutic trials in these disorders. To achieve these objectives the candidate will: 1) learn clinical research methodology through didactic course work, 2) study peripheral nerve biology and the neurobiology of pain through a structured reading program, 3) undertake a mentored, patient oriented research project aimed at the development of optimal outcomes measures for clinical trials in peripheral neuropathy, 4) develop collaborative research studies aimed at understanding the neurobiology of pain in small fiber neuropathies. The mentored research project will test the hypotheses that: 1)serial measurements of epidermal nerve fiber density (ENF) and morphology are useful as outcome measures in studies of small fiber sensory neuropathy; 2) redistribution and accumulation of novel PN3 sodium channels at sensory nerve terminals occur during the transition from asymptomatic to symptomatic HIV associated distal symmetrical polyneuropathy (DSP), and that these changes contribute to the production of neuropathic pain. This research project will be carried out in a large NIH-funded cohort at high risk for HIV-associated DSP. Through the use of serial punch skin biopsies, Dr. Herrmann will compare changes in ENF density and morphology and the level of expression of novel PN3 sodium channels at sensory nerve terminals to several clinical/laboratory measures which include: a) a patient generated pain scale; b) quantitative sensory testing; c) sural nerve conduction; and d) autonomic function. Dr. Herrmann will also examine a method to simplify the analysis of skin biopsy specimens, for easier application in large clinical trials.